The neurobiology of pair bonding: Insights from a socially monogamous rodent

The formation of enduring relationships between adult mates (i.e., pair bonds) is an integral aspect of human social behavior and has been implicated in both physical and psychological health. However, due to the inherent complexity of these bonds and the relative rarity with which they are formed in other mammalian species, we know surprisingly little about their underlying neurobiology. Over the past few decades, the prairie vole (Microtus ochrogaster) has emerged as an animal model of pair bonding. Research in this socially monogamous rodent has provided valuable insight into the neurobiological mechanisms that regulate pair bonding behaviors. Here, we review these studies and discuss the neural regulation of three behaviors inherent to pair bonding: the formation of partner preferences, the subsequent development of selective aggression toward unfamiliar conspecifics, and the bi-parental care of young. We focus on the role of vasopressin, oxytocin, and dopamine in the regulation of these behaviors, but also discuss the involvement of other neuropeptides, neurotransmitters, and hormones. These studies may not only contribute to the understanding of pair bonding in our own species, but may also offer insight into the underlying causes of social deficits noted in several mental health disorders.     

The role of vasopressin in the genetic and neural regulation of monogamy

Arginine vasopressin modulates pairbond formation in the monogamous prairie vole (Microtus ochrogaster). Our laboratory has investigated the genetic and neural mechanisms by which vasopressin and its V1a receptor (V1aR) regulate social attachment between mates. Non-monogamous vole species show strikingly different distribution patterns of brain V1aR expression compared to monogamous species, and these patterns are thought to arise from species differences in the respective promoter sequences of the V1aR gene. Individual differences in prairie vole V1aR patterns may also reflect individual differences in promoter sequences. Pharmacological and genetic manipulation of the specific brain regions that express V1aR in the 'monogamous pattern' allows multilevel examination of the neural circuits that underlie pairbond formation in monogamous species. For example, V1aR are expressed in brain regions involved in reward circuitry in monogamous vole species and have been implicated in pairbonding. V1aR are also highly expressed in regions implicated in the olfactory processing of sociosexual behaviour. We hypothesize that both circuits of reward and olfactory memory underlie the cognitive mechanisms that control pairbonding. When used in conjuction, genetic and cellular analyses of a complex social behaviour can provide a coherent framework with which to examine the role of the vasopressin system in species evolution and neural control of behaviour.     

Ventral striatopallidal oxytocin and vasopressin V1a receptors in the monogamous prairie vole (Microtus ochrogaster)

Oxytocin receptors (OTR) and vasopressin V1a receptors (V1aR) in the ventral forebrain play critical roles in the formation of pair bonds in the monogamous prairie vole. Previous reports have been inconsistent in the identification of the specific brain regions in the ventral forebrain that express these receptors. To delineate more clearly the neuroanatomical boundaries of the OTR and V1aR fields in this species, we compared OTR and V1aR binding in adjacent brain sections and also with markers that delineate neuroanatomical boundaries in the ventral forebrain. OTR binding displayed an overlapping distribution with substance P mRNA and preproenkephalin mRNA, both markers for the shell and core of the nucleus accumbens. V1aR binding was nonoverlapping with each of these markers but colocalized with iron accumulation as shown by Perls' iron stain as well as leucine-enkephalin immunoreactivity, both markers for the ventral pallidum. OTR and V1aR mRNA were also restricted within the nucleus accumbens and ventral pallidum, respectively. Furthermore, destruction of ventral striatal dopaminergic terminals with 6-hydroxydopamine infusions into the nucleus accumbens did not alter OTR binding. Immunocytochemical analysis of oxytocin and vasopressin in the ventral forebrain demonstrated the presence of oxytocin-immunoreactive fibers in the nucleus accumbens and vasopressin-immunoreactive fibers in the ventral pallidum, with males showing a greater density of vasopressin fibers than females, but there was no such sex difference in the oxytocin system. Based on these results, we discuss potential neural mechanisms by which receptors in these brain regions mediate pair bond formation in this monogamous species. J. Comp. Neurol. 468:555-570, 2004.     

Neuropeptide diversity and the regulation of social behavior in New World primates

Oxytocin (OT) and vasopressin (AVP) are important hypothalamic neuropeptides that regulate peripheral physiology, and have emerged as important modulators of brain function, particularly in the social realm. OT structure and the genes that ultimately determine structure are highly conserved among diverse eutherian mammals, but recent discoveries have identified surprising variability in OT and peptide structure in New World monkeys (NWM), with five new OT variants identified to date. This review explores these new findings in light of comparative OT/AVP ligand evolution, documents coevolutionary changes in the oxytocin and vasopressin receptors (OTR and V1aR), and highlights the distribution of neuropeptidergic neurons and receptors in the primate brain. Finally, the behavioral consequences of OT and AVP in regulating NWM sociality are summarized, demonstrating important neuromodulatory effects of these compounds and OT ligand-specific influences in certain social domains.     

Comparing vasopressin and oxytocin fiber and receptor density patterns in the social behavior neural network: Implications for cross-system signaling

Vasopressin (AVP) and oxytocin (OXT) regulate social behavior by binding to their canonical receptors, the vasopressin V1a receptor (V1aR) and oxytocin receptor (OTR), respectively. Recent studies suggest that these neuropeptides may also signal via each other’s receptors. The extent to which such cross-system signaling occurs likely depends on anatomical overlap between AVP/OXT fibers and V1aR/OTR expression. By comparing AVP/OXT fiber densities with V1aR/OTR binding densities throughout the rat social behavior neural network (SBNN), we propose the potential for cross-system signaling in four regions: the medial amygdala (MeA), bed nucleus of the stria terminalis (BNSTp), medial preoptic area, and periaqueductal grey. We also discuss possible implications of corresponding sex (higher in males versus females) and age (higher in adults versus juveniles) differences in AVP fiber and OTR binding densities in the MeA and BNSTp. Overall, this review reveals the need to unravel the consequences of potential cross-system signaling between AVP and OXT systems in the SBNN for the regulation of social behavior.     

Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans.     

Relationships among estrogen receptor, oxytocin and vasopressin gene expression and social interaction in male mice

The incidence of social disorders such as autism and schizophrenia is significantly higher in males, and the presentation more severe, than in females. This suggests the possible contribution of sex hormones to the development of these psychiatric disorders. There is also evidence that these disorders are highly heritable. To contribute toward our understanding of the mechanisms underlying social behaviors, particularly social interaction, we assessed the relationship of social interaction with gene expression for two neuropeptides, oxytocin (OT) and arginine vasopressin (AVP), using adult male mice. Social interaction was positively correlated with: oxytocin receptor (OTR) and vasopressin receptor (V1aR) mRNA expression in the medial amygdala; and OT and AVP mRNA expression in the paraventricular nucleus of the hypothalamus (PVN). When mice representing extremes of social interaction were compared, all of these mRNAs were more highly expressed in high social interaction mice than in low social interaction mice. OTR and V1aR mRNAs were highly correlated with estrogen receptor α (ERα) mRNA in the medial amygdala, and OT and AVP mRNAs with estrogen receptor β (ERβ) mRNA in the PVN, indicating that OT and AVP systems are tightly regulated by estrogen receptors. A significant difference in the level of ERα mRNA in the medial amygdala between high and low social interaction mice was also observed. These results support the hypothesis that variations of estrogen receptor levels are associated with differences in social interaction through the OT and AVP systems, by upregulating gene expression for those peptides and their receptors.     

Comparison of the distribution of oxytocin and vasopressin 1a receptors in rodents reveals conserved and derived patterns of nonapeptide evolution

Oxytocin (OT) and vasopressin (VP) are known modulators of social behaviour across rodents. Research has revealed the location of action of these nonapeptides through localization of their associated receptors, which include the oxytocin receptor (OTR) and the vasopressin 1a receptor (V1aR). As research into these complex systems has progressed, studies investigating how these systems modulate behaviour have remained relatively narrow in scope (ie, focused on how a single brain region shapes behaviour in only a handful of species). However, the brain regions that regulate social behaviour are part of interconnected neural networks for which coordinated activity enables behavioural variation. Thus, to better understand how nonapeptide systems have evolved under different selective pressures among rodent species, we conducted a meta‐analysis using a multivariate comparative method to examine the patterns of OTR and V1aR density expression in this taxon. Several brain regions were highly correlated based on their OTR and V1aR binding patterns across species, supporting the notion that the distribution of these receptors is highly conserved in rodents. However, our results also revealed that specific patterns of V1aR density differed from OTR density, and within‐genus variance for V1aR was low compared to between‐genus variance, suggesting that these systems have responded and evolved quite differently to selective pressures over evolutionary time. We propose that, in addition to examining single brain regions of interest, taking a broad comparative approach when studying the OT and VP systems is important for understanding how the systemic action of nonapeptides modulate social behaviour across species.     

Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice

The arginine vasopressin (AVP) system plays an important role in social behavior. Autism, with its hallmark disturbances in social behavior, has been associated with the V1a receptor (V1aR) gene. Furthermore, impairments of social function are often observed in symptoms of schizophrenia. Subchronic phencyclidine (PCP) produces behaviors relating to certain aspects of schizophrenic symptoms such as impairing social interaction in animals and it reduces the density of V1aR binding sites in several brain regions. Here, we report that V1aR knockout (KO) mice exhibited impairment of social behavior in a social interaction test, and showed reduced anxiety-related behavior in elevated plus-maze and marble-burying behavior tests. Given the current findings, the V1aR may be involved in the regulation of social interaction, and V1aR KO mice could be used as an animal model of psychiatric disorders associated with social behavior deficits, such as autism and schizophrenia.     

The neurobiology of social recognition, approach, and avoidance.

Rodent models of social behavior provide powerful experimental tools for elucidating the molecular, cellular, and neurobiological mechanisms regulating social behavior. Here I discuss several rodent models that have been particularly useful in understanding the neurobiology of the discrimination of social verses nonsocial stimuli, affiliative behavior, and social avoidance. The oxytocin knockout mouse model has been useful for understanding how, in the context of social recognition, the brain may process social stimuli differently from nonsocial stimuli. Vole species that are either highly social and monogamous or solitary and promiscuous have provided a model for investigating the brain mechanisms involved in promoting social interactions. Comparative studies in these species strongly implicate the neuropeptides oxytocin and vasopressin in the regulation of affiliative behavior as well as social attachment. A conditioned defeat model in hamsters may provide a useful model to understand how adverse social experiences may facilitate social avoidance. These models have yielded valuable insights into the regulation of social behaviors, and the findings of these studies may prove useful in understanding the neural mechanisms that underlie individual differences in human personality traits.     

Oxytocin and vasopressin receptor distributions in a solitary and a social species of tuco-tuco (Ctenomys haigi and Ctenomys sociabilis)

The neuropeptides oxytocin and vasopressin and their receptors have been implicated in elements of mammalian social behavior such as attachment to mates and offspring, but their potential role in mediating other types of social relationships remains largely unknown. We performed receptor autoradiography to assess whether forebrain oxytocin receptor (OTR) or vasopressin V1a receptor (V1aR) distributions differed with social structure in two closely related and ecologically similar species of South American rodents, the colonial tuco-tuco (Ctenomys sociabilis) and the Patagonian tuco-tuco (Ctenomys haigi). Long-term field studies have revealed that C. haigi is solitary, whereas C. sociabilis is social and provides a model of female-based group living. Our analyses revealed marked differences in OTR and V1aR distributions between these species. For example, only C. sociabilis had OTR binding in the piriform cortex and thalamus and V1aR binding in the olfactory bulbs. In contrast, C. haigi exhibited dramatically higher levels of OTR binding throughout the lateral septum and hippocampus. More generally, the group-living C. sociabilis exhibited a pattern of nucleus accumbens OTR and ventral pallidum V1aR binding different from that associated with the formation of opposite-sex pair bonds in microtine rodents. Higher binding in the central nucleus of the amygdala of C. sociabilis was consistent with the hypothesis that formation of social groups in C. sociabilis may be facilitated by reduced social anxiety. Low OTR binding in the lateral septum might also be a permissive factor for group living in C. sociabilis. Future studies will expand on these analyses to explore interspecific differences in ctenomyid receptor binding patterns in a phylogenetic context.     

Species and sex differences in brain distribution of corticotropin-releasing factor receptor subtypes 1 and 2 in monogamous and promiscuous vole species

Corticotropin-releasing factor (CRF) receptor subtypes 1 and 2 have been implicated in rodent models of anxiety, but much less is known about the CRF system and social behavior. Both corticosterone and central CRF receptors modulate pair bonding in the monogamous prairie vole. Using receptor autoradiography, we mapped CRFR(1) and CRFR(2) in the brains of two monogamous vole species, the prairie vole and pine vole, and two promiscuous vole species, the meadow vole and montane vole. We found markedly different patterns of brain CRFR(1) and CRFR(2) binding among the four species, including species differences in the olfactory bulb, nucleus accumbens, lateral septum, hippocampus, laterodorsal thalamus, cingulate cortex, superior colliculus, and dorsal raphe. Interestingly, we also observed striking sex differences in voles: CRFR(2) binding was higher in the encapsulated bed nucleus of the stria terminalis in males than females for all four vole species. These results suggest possible sites of action for CRF-induced facilitation of pair bond formation in prairie voles, as well as potential sex differences in the CRF modulation of pair bonding. Further examination of CRF receptors in vole species may reveal a novel role for CRF in social behavior. Ultimately, our results identify several brain regions with conserved CRF receptor patterns across rodent and primate species, in contrast to several brain regions with phylogenetically plastic CRF receptor patterns, and have interesting implications for the evolution of CRF receptor patterns and behavior.     

Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men

The neural mechanisms supporting social bonds between adult men remain uncertain. In this double-blind, placebo-controlled study, we investigate the impact of intranasally administered oxytocin (OT) and vasopressin (AVP) on behavior and brain activity among men in the context of an iterated Prisoner's Dilemma game, which models a real-life social situation. fMRI results show that, relative to both AVP and placebo, OT increases the caudate nucleus response to reciprocated cooperation, which may augment the reward of reciprocated cooperation and/or facilitate learning that another person can be trusted. OT also enhances left amygdala activation in response to reciprocated cooperation. Behaviorally, OT was associated with increased rates of cooperation following unreciprocated cooperation in the previous round compared with AVP. AVP strongly increased cooperation in response to a cooperative gesture by the partner compared with both placebo and OT. In response to reciprocated cooperation, AVP increased activation in a region spanning known vasopressin circuitry implicated in affiliative behaviors in other species. Finally, both OT and AVP increase amygdala functional connectivity with the anterior insula relative to placebo, which may increase the amygdala's ability to elicit visceral somatic markers that guide decision making. These findings extend our knowledge of the neural and behavioral effects of OT and AVP to the context of genuine social interactions.     

The neurobiology of social bonds

When released in the brain through giving birth or mating, the neuropeptides oxytocin and vasopressin are involved in promoting parent-offspring and monogamous bonds in animals such as sheep and voles. Bonds are only formed in species where receptors for these neuropeptides are highly expressed in dopamine-producing reward centres. In humans, dysfunctions in these same systems can be associated with autism and, when we see people we love, these systems become activated.     

Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: A quantitative comparative study

The genus Microtus includes several closely related species of voles with diverse patterns of social organization. Comparative studies of these species have previously tested hypotheses related to the evolution of monogamy and affiliation. In earlier studies, monogamous voles have been reported to differ from closely related nonmonogamous voles in the neural distribution of oxytocin and vasopressin receptors. These receptors have also been implicated in the behavioral differences relevant to monogamy, as oxytocin and vasopressin influence pair-bond formation in the monogamous species. In the current study, two monogamous and two nonmonogamous vole species were compared for the distribution of oxytocin and vasopressin immunoreactivity. Contrary to our predictions, gender dimorphisms in vasopressin immunoreactivity were as evident in the monogamous as in the nonmonogamous species. Also, species differences in oxytocin and vasopressin staining were subtle relative to the profound species differences previously reported for receptor binding. These results are consistent with the hypothesis that neuroendocrine systems may evolve by changes in receptor distribution rather than by restructuring the presynaptic pathway. © 1996 Wiley-Liss, Inc.     

Stability and Dynamics of Forebrain Vasopressin Receptor and Oxytocin Receptor During Pregnancy in Prairie Voles

During pregnancy, females undergo several physiologically driven changes that facilitate adaptive behaviours and prepare the mother to care for her developing offspring. The nonapeptide hormone oxytocin is best recognised for its involvement in mammalian pregnancy and has been tightly associated with maternal care, in addition to its roles in pregnancy, parturition and lactation. A closely-related nonapeptide hormone, arganine vasopressin, has received considerably less attention for its role in pregnancy, although it has recently been implicated in modulating maternal care and aggression. In the present study, we examined the expression patterns of receptors for oxytocin (OXTR) and vasopressin (V1aR) over the course of pregnancy, ranging from non-mated virgin to immediately postpartum female prairie voles (Microtus ochrogaster). Unexpectedly, we found that OXTR was highly stable in all measured structures in the forebrain. V1aR was also stable throughout most of the brain. Two exceptions to this were found in the ventral pallidum (VPall) and the paraventricular nucleus of the hypothalamus (PVN); both significantly correlated with the length of time that females were pregnant. Changes in the PVN may reflect functional feedback in vasopressin release, or preparatory changes for ensuing maternal behaviour. The results also indicate an unappreciated role for VPall V1aR in pregnancy, which may relate to the function of the VPall in hedonic ‘liking’ and motivational ‘wanting.’ Taken together, our data indicate that, with a few compelling exceptions, nonapeptide dynamics during prairie vole pregnancy are largely limited to changes in the synthesis and release of oxytocin and vasopressin, and not the receptors to which they bind.     

Centrally mediated effects of neurohypophyseal hormones

The neurohypophyseal hormones oxytocin and vasopressin cause a variety of biological effects in animals which are mediated by central nervous system mechanisms. Among the best studied of these effects is the modulation of both memory processes and the development of drug tolerance and dependence. Neurohypophyseal hormones have also been shown to alter various physiological parameters such as heart rate and body temperature following central administration. In addition, these peptides can profoundly alter spontaneous, unlearned behavior in several rodent species. Many of the centrally mediated effects of neurohypophyseal hormones have been shown to be elicited at sites within the brain stem and the limbic system where vasopressin and oxytocin occur in cell bodies, axons and nerve terminals, suggesting a physiological role for these peptide effects. The various central effects of neurohypophyseal hormones involve different mechanisms which can be distinguished from one another on the basis of required dose, time-course of action, and structure-activity relationships. Thus, alterations of spontaneous behavior are mediated by putative receptors closely related to vasopressin receptors in blood vessels responsible for the peripheral pressor response while the effects on memory processes are mediated by a mechanism which is not closely related to those involved in the peripheral hormonal effects of the peptides. The influence of neurohypophyseal hormones on memory and attention may be useful clinically. A potential role for these peptides in mental disorders is discussed.     

Autoradiographic detection of vasopressin binding sites, but not of oxytocin binding sites, in the sheep olfactory bulb

Oxytocin facilitates maternal behaviour in sheep. In the present study, we searched for the presence of oxytocin and vasopressin binding sites in the sheep olfactory bulb, a brain area which is thought to be involved in specific bond formation between the ewe and its lamb. Using in vitro autoradiography, we observed binding of tritiated vasopressin to the glomerular layer of the olfactory bulb. Competition studies performed with structural analogues and the use of a 125I-labelled linear vasopressin antagonist suggested that sites which bind vasopressin are V1 type receptors. In contrast, specific binding sites for oxytocin in the olfactory bulb could be detected neither in control females, nor in ovariectomized females treated with estradiol nor in postparturient ewes, although such sites were present in the uterus.     

Behavioral and cardiovascular consequences of disrupted oxytocin communication in cohabitating pairs of male and female prairie voles

ABSTRACT

Negative social experiences may influence psychological and physiological health via altered central oxytocin communication. The prairie vole is valuable for investigating the potential influence of oxytocin on responses to social experiences. Prairie voles are socially monogamous, live in pairs or family groups, and respond negatively to changes in the social environment. This study investigated the hypothesis that disruptions of oxytocin in one prairie vole of a cohabitating male-female pair would alter social behavior in that specific animal; and these behavioral changes in turn would influence the untreated partner’s behavior and physiology. Pharmacological antagonism of oxytocin with the receptor antagonist L-368,899 in the male prairie vole disrupted social behaviors between the male and his untreated female partner. This manipulation also negatively influenced the behavior and cardiovascular function in the untreated female partner, including increased: (a) depression-relevant behaviors in two behavioral stressors, (b) basal mean arterial pressure and heart rate, and (c) cardiovascular reactivity to the behavioral stressors. These results suggest that disruptions of oxytocin and social behavior in one animal may produce indicators of social stress in an untreated social partner. This preliminary research provides a foundation for future studies to investigate mechanisms underlying responses to social experiences in humans.